In sub-Saharan Africa, the intersection between the HIV epidemic and the endemic nature of Kaposi's sarcoma-associated herpesvirus (KSHV) infection has caused Kaposi's sarcoma (KS) to become the most common malignancy in many parts of the region. In HIV-infected patients with KS in resource-rich areas, use of highly active antiretroviral therapy (HAART) often causes regression of KS even in the absence of conventional chemotherapy. However, it is not known which specific antiretroviral drugs are critical to convey HAART's effect on KS and how HAART achieves this effect. In particular, recent data from in vitro systems and animal models suggest that protease inhibitors (Pis), originally developed to block the active site of HIV aspartyl protease, also have direct anti-KS effects. Now that antiretroviral therapy is becoming available in Africa, it is important to address the hypothesis that Pi-containing HAART is superior to Pi- sparing HAART in promoting KS regression. Hence, our multidisciplinary team proposes these four aims: (1) Determine whether a Pi-based HAART regimen (lopinavir/ritonavir plus zidovudine/lamivudine) is more efficacious than a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen (efavirenz plus zidovudine/lamivudine) in promoting the regression of KS tumor burden in persons with AIDS-related KS in Africa; (2) Evaluate which pre-HAART parameters are predictive of KS regression among HAART-treated patients with KS in Africa and how changes in these parameters after HAART is initiated predict KS regression; (3) Examine the effect of HAART, when used in African patients with AIDS-related KS, on KSHV-related virologic activity and host immune response to KSHV, including whether the use of HAART reduces levels of KSHV salivary shedding and therefore potentially reduces KSHV infectiousness; and (4) Estimate the incidence and determinants of KS-associated immune reconstitution inflammatory syndrome in patients with AIDS-related KS in Africa who are treated with HAART. To achieve these aims, we will perform a randomized trial of a Pi-based HAART regimen versus an NNRTI-based HAART regimen among 224 antiretroviral-naTve persons with non-chemotherapy-requiring AIDS-related KS in Kampala, Uganda. Subjects will be followed at four-week intervals for 48 weeks, and the primary outcome will be a blinded measurement of the change in KS tumor burden. We will also longitudinally assess the response to HAART in terms of changes in KSHV DMA levels in saliva and blood, host humoral and cellular immune response to KSHV, and plasma levels of VEGF, bFGF, and MMP-2. Findings from this work will both help to inform clinical care of patients with AIDS-related KS in Africa and provide biological insights into the effect of antiretroviral therapy on underlying KSHV infection.